Infrared ATR glucose measurement system (II)

ABSTRACT

This involves a non-invasive glucose measurement device and a process for determining blood glucose level in the human body using the device. In typical operation, the glucose measurement device is self-normalizing in that it does not employ an independent reference sample in its operation. The device uses attenuated total reflection (ATR) infrared spectroscopy. Preferably, the device is used on a fingertip and compares two specific regions of a measured infrared spectrum to determine the blood glucose level of the user. Clearly, this device is especially suitable for monitoring glucose levels in the human body, and is especially beneficial to users having diabetes mellitus. The device and procedure may be used for other analyte materials which exhibit unique mid-IR signatures of the type described herein and that are found in appropriate regions of the outer skin.

RELATED APPLICATIONS

[0001] This is a continuation of U.S. patent application Ser. No.09/547,433, filed Apr. 12, 2000, which is a continuation-in-part ofPCT/US99/23823, filed Oct. 12, 1999, designating the U.S., which in turnderives benefit from U.S. Application Serial. No. 60/103,883, to Bermanand Roe, filed Oct. 13, 1998, each of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

[0002] This invention involves a non-invasive glucose measurement deviceand a process for determining blood glucose level in the human bodyusing the device. In typical operation, the glucose measurement deviceis self-normalizing in that it does not employ an independent referencesample in its operation. The inventive device uses attenuated totalreflection (ATR) infrared spectroscopy. Preferably, the device is usedon a fingertip or other part of the body. Although the inventiveprocedure preferably compares two specific regions of a measuredmid-infrared spectrum to determine the blood glucose level of the user.Clearly, this device is especially suitable for monitoring glucoselevels in the human body, and is especially beneficial to users havingdiabetes mellitus. The device and procedure may be used for othermaterials which exhibit unique mid-IR signatures of the type describedbelow and that are found in appropriate regions of the outer skin. Acleaning kit and related procedure for preparation of the skin surfaceis also included.

BACKGROUND OF THE INVENTION

[0003] The American Diabetes Association reports that nearly 6% of thepopulation in the United States, a group of 16 million people, hasdiabetes. The Association further reports that diabetes is the seventhleading cause of death in the United States, contributing to nearly200,000 deaths per year. Diabetes is a chronic disease having no cure.The complications of the disease include blindness, kidney disease,nerve disease, and heart disease, perhaps with stroke. Diabetes is saidto be the leading cause of new cases of blindness in individuals in therange of ages between 20 and 74; from 12,000-24,000 people per year losetheir sight because of diabetes. Diabetes is the leading cause ofend-stage renal disease, accounting for nearly 40% of new cases. Nearly60-70% of people with diabetes have mild to severe forms of diabeticnerve damage which, in severe forms, can lead to lower limb amputations.People with diabetes are 2-4 times more likely to have heart disease andto suffer strokes.

[0004] Diabetes is a disease in which the body does not produce orproperly use insulin, a hormone needed to convert sugar, starches, andthe like into energy. Although the cause of diabetes is not completelyunderstood, genetics, environmental factors, and viral causes have beenpartially identified.

[0005] There are two major types of diabetes: Type I and Type II. Type Idiabetes (formerly known as juvenile diabetes) is an autoimmune diseasein which the body does not produce any insulin and most often occurs inyoung adults and children. People with Type I diabetes must take dailyinsulin injections to stay alive.

[0006] Type II diabetes is a metabolic disorder resulting from thebody's inability to make enough, or properly to use, insulin. Type IIdiabetes accounts for 90-95% of diabetes. In the United States, Type IIdiabetes is nearing epidemic proportions, principally due to anincreased number of older Americans and a greater prevalence of obesityand a sedentary lifestyle.

[0007] Insulin, in simple terms, is the hormone that unlocks the cellsof the body, allowing glucose to enter those cells and feed them. Since,in diabetics, glucose cannot enter the cells, the glucose builds up inthe blood and the body's cells literally starve to death.

[0008] Diabetics having Type I diabetes typically are required toself-administer insulin using, e.g., a syringe or a pin with needle andcartridge. Continuous subcutaneous insulin infusion via implanted pumpsis also available. Insulin itself is typically obtained from porkpancreas or is made chemically identical to human insulin by recombinantDNA technology or by chemical modification of pork insulin. Althoughthere are a variety of different insulins for rapid-, short-,intermediate-, and long-acting forms that may be used variously,separately or mixed in the same syringe, use of insulin for treatment ofdiabetes is not to be ignored.

[0009] It is highly recommended by the medical profession thatinsulin-using patients practice self-monitoring of blood glucose (SMBG).Based upon the level of glucose in the blood, individuals may makeinsulin dosage adjustments before injection. Adjustments are necessarysince blood glucose levels vary day to day for a variety of reasons,e.g., exercise, stress, rates of food absorption, types of food,hormonal changes (pregnancy, puberty, etc.) and the like. Despite theimportance of SMBG, several studies have found that the proportion ofindividuals who self-monitor at least once a day significantly declineswith age. This decrease is likely due simply to the fact that thetypical, most widely used, method of SMBG involves obtaining blood froma finger stick. Many patients consider obtaining blood to besignificantly more painful than the self-administration of insulin.

[0010] There is a desire for a less invasive method of glucosemeasurement. Methods exist or are being developed for a minimallyinvasive glucose monitoring, which use body fluids other than blood(e.g., sweat or saliva), subcutaneous tissue, or blood measured lessinvasively. Sweat and saliva are relatively easy to obtain, but theirglucose concentration appears to lag in time significantly behind thatof blood glucose. Measures to increase sweating have been developed andseem to increase the timeliness of the sweat glucose measurement,however.

[0011] Subcutaneous glucose measurements seem to lag only a few minutesbehind directly measured blood glucose and may actually be a bettermeasurement of the critical values of glucose concentrations in thebrain, muscle, and in other tissue. Glucose may be measured bynon-invasive or minimally-invasive techniques, such as those making theskin or mucous membranes permeable to glucose or those placing areporter molecule in the subcutaneous tissue. Needle-type sensors havebeen improved in accuracy, size, and stability and may be placed in thesubcutaneous tissue or peripheral veins to monitor blood glucose withsmall instruments. See, “An Overview of Minimally InvasiveTechnologies”, Clin. Chem. 1992 Sep.; 38(9): 1596-1600.

[0012] Truly simple, non-invasive methods of measuring glucose are notcommercially available.

[0013] U.S. Pat. No. 4,169,676 to Kaiser, shows a method for the use ofATR glucose measurement by placing the ATR plate directly against theskin and especially against the tongue. The procedure and device shownthere uses a laser and determines the content of glucose in a specificliving tissue sample by comparing the IR absorption of the measuredmaterial against the absorption of IR in a control solution by use of areference prism. See, column 5, lines 31 et seq.

[0014] Swiss Patent No. 612,271, to Dr. Nils Kaiser, appears to be theSwiss patent corresponding to U.S. Pat. No. 4,169,676.

[0015] U.S. Pat. No. 4,655,255, to Dähne et al., describes an apparatusfor non-invasively measuring the level of glucose in a blood stream ortissues of patients suspected to have diabetes. The method isphotometric and uses light in the near-infrared region. Specifically,the procedure uses light in the 1,000 to 2,500 nm range. Dähne's deviceis jointly made up to two main sections, a light source and a detectorsection. They may be situated about a body part such as a finger. Thedesired near-infrared light is achieved by use of filters. The detectorsection is made up of a light-collecting integrating sphere orhalf-sphere leading to a means for detecting wavelengths in thenear-infrared region. Dähne et al. goes to some lengths teaching awayfrom the use of light in the infrared range having a wavelength greaterthan about 2.5 micrometers since those wavelengths are strongly absorbedby water and have very little penetration capability into living tissuescontaining glucose. That light is said not to be “readily useable toanalyze body tissue volumes at depths exceeding a few microns or tens ofmicrons.” Further, Dähne et al. specifically indicates that an ATRmethod which tries to circumvent the adverse consequences of the heateffect by using a total internal reflection technique is able only toinvestigate to tissue depths not exceeding about 10 micrometers, a depthwhich is considered by Dähne et al. to be “insufficient to obtainreliable glucose determination information.”

[0016] U.S. Pat. No. 5,028,787, to Rosenthal et al., describes anon-invasive glucose monitoring device using near-infrared light. Thelight is passed into the body in such a way that it passes through someblood-containing region. The so-transmitted or reflected light is thendetected using an optical detector. The near-infrared light sources arepreferably infrared emitting diodes (IRED). U.S. Pat. No. 5,086,229 is acontinuation in part of U.S. Pat. No. 5,028,787.

[0017] U.S. Pat. No. 5,178,142, to Harjunmaa et al, teaches the use of astabilized near-infrared radiation beam containing two alternatingwavelengths in a device to determine a concentration of glucose or otherconstituents in a human or animal body. Interestingly, one of thetransmitted IR signals is zeroed by variously tuning one of thewavelengths, changing the extracellular to intracellular fluid ratio ofthe tissue by varying the mechanical pressure on a tissue. Or, the ratiomay be allowed to change as a result of natural pulsation, e.g., byheart rate. The alternating component of the transmitted beam ismeasured in the “change to fluid ratio” state. The amplitude of thevarying alternating signal is detected and is said to represent glucoseconcentration or is taken to represent the difference in glucoseconcentration from a preset reference concentration.

[0018] U.S. Pat. No. 5,179,951 and its divisional, U.S. Pat. No.5,115,133, to Knudson, show the application of infrared light formeasuring the level of blood glucose in blood vessels in the tympanicmembrane. The detected signal is detected, amplified, decoded, and,using a microprocessor, provided to a display device. The infrareddetector (No. 30 in the drawings) is said simply to be a “photo diodeand distance signal detector” which preferably includes “means fordetecting the temperature of the volume in the ear between the detectorand the ear's tympanic membrane.” Little else is said about theconstituency of that detector.

[0019] U.S. Pat. No. 5,433,197, to Stark, describes a non-invasiveglucose sensor. The sensor operates in the following fashion. Anear-infrared radiation is passed into the eye through the cornea andthe aqueous humor, reflected from the iris or the lens surface, and thenpassed out through the aqueous humor and cornea. The reflected radiationis collected and detected by a near-infrared sensor which measures thereflected energy in one or more specific wavelength bands. Comparison ofthe reflected energy with the source energy is said to provide a measureof the spectral absorption by the eye components. In particular, it issaid that the level of glucose in the aqueous humor is a function of thelevel of glucose in the blood. It is said in Stark that the measuredglucose concentration in the aqueous humor tracks that of the blood by afairly short time, e.g., about 10 minutes. The detector used ispreferably a photodiode detector of silicon or InGaAs. The infraredsource is said preferably to be an LED, with a refraction grating sothat the light of a narrow wavelength band, typically 10 to 20nanometers wide, passes through the exit slit. The light is in thenear-infrared range. The use of infrared regions below 1400 nanometersand in the region between 1550 and 1750 nanometers is suggested.

[0020] U.S. Pat. No. 5,267,152, to Yang et al., shows a non-invasivemethod and device for measuring glucose concentration. The method andapparatus uses near-infrared radiation, specifically with a wavelengthof 1.3 micrometers to 1.8 micrometers from a semiconductor diode laser.The procedure is said to be that the light is then transmitted downthrough the skin to the blood vessel where light interacts with variouscomponents of the blood and is then diffusively reflected by the bloodback through the skin for measurement.

[0021] Similarly, U.S. Pat. No. 5,313,941, to Braig et al., suggests aprocedure and apparatus for monitoring glucose or ethanol and otherblood constituents in a non-invasive fashion. The measurements are madeby monitoring absorption of certain constituents in the longer infraredwavelength region. The long wavelength infrared energy is passed throughthe finger or other vascularized appendage. The infrared light passingthrough the finger is measured. The infrared source is pulsed to preventburning or other patient discomfort. The bursts are also synchronizedwith the heartbeat so that only two pulses of infrared light are sentthrough the finger per heartbeat. The detected signals are then analyzedfor glucose and other blood constituent information.

[0022] U.S. Pat. No. 5,398, 681, to Kuperschmidt, shows a device whichis said to be a pocket-type apparatus for measurement of blood glucoseusing a polarized-modulated laser beam. The laser light is introducedinto a finger or ear lobe and the phase difference between a referencesignal and the measurement signal is measured and processed to formulateand calculate a blood glucose concentration which is then displayed.

[0023] U.S. Pat. No. 6,001,067 shows an implantable device suitable forglucose monitoring. It utilizes a membrane which is in contact with athin electrolyte phase, which in turn is covered by an enzyme-containingmembrane, e.g., glucose oxidase in a polymer system. Sensors arepositioned in such a way that they measure the electrochemical reactionof the glucose within the membranes. That information is then passed tothe desired source.

[0024] None of the cited prior art suggests the device and method ofusing this device described and claimed below.

SUMMARY OF THE INVENTION

[0025] This invention is a glucose level measurement device utilizingIR-ATR spectroscopy and a method of using the device. The inventivedevice itself is preferably made up of four parts:

[0026] a.) an IR source for emitting an IR beam into the ATR plate,

[0027] b.) the ATR plate against which the sampled human skin surface ispressed, and

[0028] c.) at least two IR sensors for simultaneously measuringabsorbance of two specific regions of the IR spectrum, i.e., a“referencing wavelength” and a “measuring wavelength.” The IR sourcemust emit IR radiation at least in the region of the referencingwavelength and the measuring wavelength. For glucose, the referencingwavelength is between about 8.25 micrometers and about 8.75 micrometersand the measuring wavelength is between about 9.50 micrometers and about10.00 micrometers. The IR sources may be broadband IR sources, non-lasersources, or two or more selected wavelength lasers.

[0029] Other analyte materials which have both referencing wavelengthsand measuring wavelengths as are described in more detail below and thatpreferably are found in the outer regions of the skin may be measuredusing the inventive devices and procedures described herein.

[0030] The ATR plate is configured to permit multiple internalreflections, perhaps 3-15 internal reflections or more, against saidmeasurement surface prior to measurement by the IR sensors. Typicallythe IR beam emitted from the ATR plate is split for the IR sensors usinga beam splitter or equivalent optical device. Once the split beams aremeasured by the IR sensors, the resulting signals are then transformedusing analog comparators or digital computers into readable ordisplayable values.

[0031] It is usually important that the device have some accommodationfor holding the body part against the ATR plate, preferably at somevalue which is constant and above a selected minimum pressure.

[0032] The method for determining the blood glucose level, using theglucose measurement device, comprises the steps of.

[0033] a.) contacting a selected skin surface with the ATR plate,

[0034] b.) irradiating that human skin surface with an IR beam havingcomponents at least in the region of the referencing wavelength and themeasuring wavelength, and

[0035] c.) detecting and quantifying those referencing and saidmeasuring wavelength components in that reflected IR beam.

[0036] The procedure ideally includes the further steps of maintainingthe skin surface on said ATR plate at an adequate pressure which is bothconstant and above a selected minimum pressure and, desirably cleaningthe skin surface before measurement. A step of actually measuring thepressure may also be included.

[0037] A normalizing step practiced by simultaneously detecting andquantifying the referencing and measuring wavelength components prior tocontacting the skin surface is also desirable.

[0038] A final portion of this invention is a cleaning kit used forcleaning the object skin prior to testing and a process of using thatkit. The kit usually is made up of sealed packets, preferably containingabsorbent pads, of:

[0039] a.) a glucose solvent, e.g., water and/or other highly polarsolvent and perhaps containing a weak acid,

[0040] b.) a solvent for removing the glucose solvent, e.g.,isopropanol, and

[0041] c.) a skin softener or pliability enhancer, e.g., various mineraloils such as “Nujol”, not having significant IR wavelength peaks betweenabout 8.25 micrometers and about 8.75 micrometers or between about 9.50micrometers and about 10.00 micrometers. I prefer to mix components b.)and c.). The solvent for removing the glucose solvent similarly shouldnot have an interfering IR signal which persists after several minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

[0042]FIGS. 1A, 1B, 1C, and 1D show a side view of various ATR platesand their general operation.

[0043]FIG. 2 shows an IR spectrum of d-glucose.

[0044]FIG. 3 shows a schematicized layout of the optics of the inventivedevice.

[0045]FIG. 4 shows a packaged variation of the inventive glucosemeasuring device.

[0046]FIG. 5 shows a graph of pressure on the ATR crystal vs. IR value.

[0047]FIG. 6 shows a graph correlating glucose levels measured using aspecific variation of the device with glucose levels in the blooddetermined using a commercial device.

[0048]FIG. 7 shows a graph using a transmittance trough as thereferencing wavelength.

[0049]FIG. 8 shows a pair of glucose IR curves (taken before and aftereating) for an individual having diabetes made using the inventiveglucose measuring device.

[0050]FIG. 9 shows a graph comparing glucose levels in a non-diabeticindividual (taken before and after eating) made using the inventiveglucose measuring device and direct blood measurement. This graph showsthat the inventive procedure tracks blood glucose levels with minimumtime lag.

DESCRIPTION OF THE INVENTION

[0051] The device in this invention uses infrared (“IR”) attenuatedtotal reflectance (“ATR”) spectroscopy to detect and ultimately todetermine the level of a selected analyte, preferably blood glucose, inthe human body. Preferably, the inventive device uses an ATR procedurein which the size and configuration of the crystal permits a number ofinternal reflections before the beam is allowed to exit the crystal withits measured information. In general, as shown in FIGS. 1 A and 1B, whenan infrared beam (102) is incident on the upper surface of the ATRcrystal (104)—or ATR plate—at an angle which exceeds a critical angleΘ_(C), the beam (102) will be completely totally reflected withincrystal (104). Each reflection of the beam within the ATR plate, andspecifically against the upper surface (114), provides a bit moreinformation about the composition of the sample (112) resting againstthat upper surface (114). The more numerous the reflections, and thegreater the penetration depth of the reflection, the higher is thequality of the information. The incident beam (102) becomes reflectedbeam (106) as it exits crystal (104) as shown in FIG. 1A. Higherrefractive index materials are typically chosen for the ATR crystal tominimize the critical angle. The critical angle is a function of therefractive indices of both the sample and the ATR crystal and is definedas: $\Theta_{C} = {\sin^{- 1}( \frac{n_{2}}{n_{1}} )}$

[0052] Here, n₁ is the refractive index of the ATR crystal and n₂ is therefractive index of the sample.

[0053] Throughout this specification, we refer to wavelength measures asspecific values. It should be understood that we intend those values tobe bands or ranges of values, typically with a tolerance of +/−0.20micron, preferably +/−0.10 micron. For instance, a value of 8.25 micronswould mean a band of 8.15 to 8.35 microns, and perhaps 8.05 to 8.45microns depending upon the context.

[0054] As shown in FIG. 1B, the internally reflected beam (108) includesan evanescent wave (110) which penetrates a short distance into sample(112) over a wide wavelength range. In those regions of the IR spectrumin which the sample absorbs IR, some portion of the light does notreturn to the sensor. It is these regions of IR absorbance which provideinformation, in this inventive device, for quantification of the glucoselevel.

[0055] We have found that the mid-IR spectrum does not penetrate intothe skin to an appreciable level. Specifically, the skin is made up of anumber of layers: the outermost—the stratum cornea—is a layersubstantially free of cholesterol, water, gamma globulin, albumin, andblood. It is a shallow outer region covering the stratum granulosum, thestratum spinosum, and the basal layer. The area between the basal layerto the outside is not vascularized. It is unlikely that any layer otherthan the stratum cornea is traversed by the mid-IR light involved inthis inventive device. Although we do not wish to be bound by theory, itis likely that the eccrine or sweat glands transport the glucose to theouter skin layers for measurement and analysis by our inventions.

[0056] We prefer the use of higher refractive index crystals such aszinc selenide, zinc sulfide, diamond, germanium, and silicon as the ATRplate. The index of refraction of the ATR plate (104) should besignificantly higher than that of the sample (112).

[0057] Further, the ATR crystal (104) shown in FIG. 1A is shown to betrapezoidal and having an upper surface (114) for contact with thesample, which sample, in this case, is skin from a living human body.However, this shape is only for the purposes of mechanical convenienceand ease of application into a working commercial device. Other shapes,in particular, a parallelogram (111) such as shown in FIG. 1C and thereflective crystal (113) shown in FIG. 1D having mirrored end (115), arealso quite suitable for this inventive device should the designer sorequire. The mirrored reflective crystal (113) has the advantage of, andperhaps the detriment of having both an IR source and the IR sensors atthe same end of the crystal.

[0058] It is generally essential that the ATR crystal or plate (104)have a sample or upper surface (114) which is essentially parallel tothe lower surface (116). In general, the ATR plate (104) is preferablyconfigured and utilized so that the product of the practical number ofinternal reflections of internal reflected beam (108) and the skinpenetration per reflection of this product is maximized. When maximizingthis product, called the effective pathlength (EPL), the informationlevel in beam (106) as it leaves ATR plate (104) is significantlyhigher. Further, the higher the value of the index of refraction, n₂ ,of the ATR plate (104), the higher is the number of internalreflections. The sensitivity of the IR sensors also need not be as highwhen the EPL is maximized. We consider the number of total reflectionswithin the crystal to be preferably from 3-15 or more for adequateresults.

[0059] We have surprisingly found that a glucose measuring device madeaccording to this invention is quite effective on the human skin of thehands and fingers. We have found that the glucose concentration asmeasured by the inventive devices correlates very closely with theglucose concentration determined by a direct determination from a bloodsample. As will be discussed below, the glucose level as measured by theinventive device also is surprisingly found closely to track the glucoselevel of blood in time as well. This is surprising in that the IR beamlikely passes into the skin, i.e., the stratum corneum, for only a fewmicrons. It is unlikely in a fingertip that any blood is crossed by thatlight path. As discussed above, the stratum corneum is the outer layerof skin and is substantially unvascularized. The stratum corneum is thefinal outer product of epidermal differentiation or keratinization. Itis made up of a number of closely packed layers of flattened polyhedralcorneocytes (also known as squames). These cells overlap and interlockwith neighboring cells by ridges and grooves. In the thin skin of thehuman body, this layer may be only a few cells deep, but in thickerskin, such as may be found on the toes and feet, it may be more than 50cells deep. The plasma membrane of the corneocyte appears thickenedcompared with that of keratinocytes in the lower layers of the skin, butthis apparent deposition of a dense marginal band formed bystabilization of a soluble precursor, involucrin, just below the stratumcorneum.

[0060] It is sometimes necessary to clean the skin exterior prior beforesampling to remove extraneous glucose from the skin surface. When doingso, it is important to select cleaning materials which have IR spectrathat do not interfere with the IR spectra of glucose. We consider a kitof the following to be suitable for preparation of the sample skin forthe testing. The components are: a.) a glucose solvent, e.g., water orother highly polar solvent; b.) a solvent for removing the water, e.g.,isopropanol, and c.) a skin softener or pliability enhancer not havingsignificant IR peaks in the noted IR regions, e.g., mineral oils such asthose sold as “Nujol”. Preferably the b.) and c.) components areadmixed, although they need not be. Certain mixtures of the first twocomponents may be acceptable, but only if the sampling situation is suchthat the solvents evaporate without spectrographically significantresidue. We have also found that soap and its residue are sometimes aproblem. Consequently, addition of a weak acid again not havingsignificant IR peaks in the noted IR regions, to the a.) component,i.e., the solvent for removing glucose, is desirable. The preferred weakacid is boric acid. The inventive kit preferably is made up of sealedpackets of the components, most preferably each packet containing anabsorbent pad.

[0061] Additionally, the inventive device can be highly simplifiedcompared to other known devices in that the device can be“self-normalizing” due to the specifics of the IR signature of glucose.FIG. 2 shows the IR absorbance spectra of d-glucose. The family ofcurves there shows that in certain regions of the IR spectrum, there isa correlation between absorbance and the concentration of glucose.Further, there is a region in which the absorbance is not at alldependent upon the concentration of glucose. Our device, in itspreferable method of use, uses these two regions of the IR spectra.These regions are in the so-called mid-IR range, i.e., wavelengthsbetween 2.5 and 14 micrometers. In particular, the “referencingwavelength” point is just above 8 micrometers (150), e.g., 8.25 to 8.75micrometers, and the pronounced peaks (152) at the region between about9.50 and 10.00 micrometers is used as a “measuring wavelength”. Thefamily of peaks (152) may be used to determine the desired glucoseconcentration.

[0062] Use of the two noted IR regions is also particularly suitablesince other components typically found in the skin, e.g., water,cholesterol, etc., do not cause significant measurement error when usingthe method described herein.

[0063]FIG. 3 shows an optical schematic of a desired variation of theinventive device. ATR crystal (104) with sample side (114) is shown andIR source (160) is provided. IR source (160) may be any of a variety ofdifferent kinds of sources. It may be a broadband IR source, one havingradiant temperatures of 300° C. to 800° C., or a pair of IR lasersselected for the two regions of measurement discussed above, or othersuitably emitted or filtered IR light sources. A single laser may not bea preferred light source in that a laser is a single wavelength sourceand the preferred operation of this device requires light sourcessimultaneously emitting two IR wavelengths. Lens (162), for focusinglight from IR source (160) into ATR plate (104), is also shown. It maybe desirable to include an additional mirror (163) to intercept aportion of the beam before it enters the ATR plate (104) and then tomeasure the strength of that beam in IR sensor (165). Measurement ofthat incident light strength (during normalization and during the samplemeasurement) assures that any changes in that value can be compensatedfor.

[0064] The light then passes into ATR plate (104) for contact with bodypart (164), shown in this instance to be the desired finger. Thereflected beam (106) exits ATR plate (104) and is then desirably splitusing beam splitter (166). Beam splitter (166) simply transmits someportion of the light through the splitter and reflects the remainder.The two beams may then be passed through, respectively, lenses (168) and(170). The so-focussed beams are then passed to a pair of sensors whichare specifically selected for detecting and measuring the magnitude ofthe two beams in the selected IR regions. Generally, the sensors will bemade up of filters (172) and (174) with light sensors (176) and (178)behind. Generally, one of the filters (172), (174) will be in the regionof the referencing wavelength and the other will be in that of themeasuring wavelength.

[0065]FIG. 4 shows perhaps a variation of this device (200) showing thefinger of the user (202) over the ATR plate (204) with a display (206).Further shown in this desirable variation (200) is a pressuremaintaining component (208). We have found that is very highly desirableto maintain a minimum threshold pressure on the body part which is to beused as the area to be measured. Generally, a variance in the pressuredoes not shift the position of the detected IR spectra, but it mayaffect the sensitivity of the overall device. Although it is possible toteach the user to press hard enough on the device to reach the minimumthreshold pressure, we have determined for each design of the device itis much more appropriate that the design of a particular variation ofthe inventive device be designed with a specific sample pressure inmind. The appropriate pressure will vary with, e.g., the size of the ATRplate and the like. A constant pressure above that minimum thresholdvalue is most desired.

[0066] The variation shown in FIG. 4 uses a simple component arm (208)to maintain pressure of the finger (202) on ATR plate (204). Othervariations within the scope of this invention may include clamps and thelike.

[0067] It should be apparent that once an appropriate pressure isdetermined for a specific design, the inventive device may include apressure sensor, e.g., (210) as is shown in FIG. 4, to measure adherenceto that minimum pressure. Pressure sensor (210) may alternatively beplaced beneath ATR plate (204). It is envisioned that normally apressure sensor such as (210) would provide an output signal which wouldprovide a “no-go/go” type of signal to the user.

[0068] Further, as shown in FIG. 5, the appropriate pressure may beachieved when using our device simply by increasing the pressure of thebody part on the ATR crystal surface until a selected, measured IR valuebecomes constant.

[0069] Method of Use

[0070] In general, the inventive device described above is used in thefollowing manner: a skin surface on a human being, for instance, theskin of the finger, is placed on the ATR plate. The skin surface isradiated with an IR beam having components at least in the two IRregions we describe above as the “referencing wavelength” and the“measuring wavelength.” The beam which ultimately is reflected out ofthe ATR plate then contains information indicative of the blood glucoselevel in the user. As noted above, it is also desirable to maintain thatskin surface on the ATR plate at a relatively constant pressure that istypically above a selected minimum pressure. This may be done manuallyor by measuring and maintaining the pressure or monitoring the constancyof a selected IR value.

[0071] Typically, the beam leaving the ATR plate is split using anoptical beam splitter into at least two beams. Each of the two beams maybe then focussed onto its own IR sensor. Each such IR sensor has aspecific filter. This is to say that, for instance, one IR sensor mayhave a filter which removes all light which is not in the region of thereferencing wavelength and the other IR sensor would have a filter whichremove all wavelengths other than those in the region of the measuringwavelength. As noted above, for glucose, the referencing wavelength istypically in the range of about 8.25 to 8.75 micrometers. For glucose,the measuring wavelength is typically between about 9.5 and 10.0micrometers.

[0072] Other analyte materials which have both referencing wavelengthsand measuring wavelengths in the mid-IR range and that are found in theouter regions of the skin may also be measured using the inventivedevices and procedures described herein.

[0073] Respective signals may be compared using analog or digitalcomputer devices. The signals are then used to calculate analyte valuessuch as blood glucose concentration using various stored calibrationvalues, typically those which are discussed below. The resultingcalculated values may then be displayed.

[0074] As noted above, it is also desirable both to clean the platebefore use and to clean the exterior surface of the skin to be sampled.Again, we have found, for instance in the early morning that theexterior skin is highly loaded with glucose which is easily removedpreferably by using the skin preparation kit, or, less preferably, bywashing the hands. Reproducible and accurate glucose measurements maythen be had in a period as short as ten minutes after cleaning the areaof the skin to be measured.

[0075] We also note that, depending upon the design of a specificvariation of a device made according to the invention, periodic at leastan initial calibration of the device, using typical blood sample glucosedeterminations, may be necessary or desirable.

[0076] Determination of blood glucose level from the informationprovided in the IR spectra is straightforward. A baseline is firstdetermined by measuring the level of infrared absorbance at themeasuring and referencing wavelengths, without a sample being present onthe sample plate. The skin is then placed in contact with the ATR plateand the two specified absorbance values are again measured. Using thesefour values, the following calculation is then made.$A_{1} = {{\ln ( \frac{T_{01}}{T_{1}} )} = {A_{g\quad 1} + {A_{b\quad 1}\quad( {{Absorbance}\quad {at}\quad {referencing}\quad {spectral}\quad {{band}.}} )}}}$${A_{2} = {{\ln ( \frac{T_{02}}{T_{2}} )} = {A_{g\quad 2} + {A_{b\quad 2}\quad ( {{Absorbance}\quad {at}\quad {measuring}\quad {spectral}\quad {{band}.}} )}}}}\quad$

[0077] where

[0078] T₀₁=measured value at reference spectral band w/o sample

[0079] T₀₂=measured value at measuring spectral band w/o sample

[0080] T₁=measured value at reference spectral band w/ sample

[0081] T₂=measured value at measuring spectral band w/ sample

[0082] A_(g1)=absorbance of glucose at reference spectral band

[0083] A_(g2)=absorbance of glucose at measuring spectral band

[0084] A_(b1)=absorbance of background at reference spectral band

[0085] A_(b2)=absorbance of background at measuring spectral band

[0086] d=effective path length through the sample.

[0087] a₂=specific absorptivity at measuring spectral band

[0088] k=calibration constant for the device

[0089] C_(g)=measured concentration of glucose

[0090] Since the background base values are approximately equal (i.e.,A_(b1)=A_(b2)) and A_(g1)=0, then:

A ₂ −A ₁ =A _(g2) =a ₂ dC _(g)

[0091] and

C _(g) =k(A ₂ −A ₁)

[0092] The value of C_(g) is the desired result of this procedure.

[0093] Similarly, FIG. 7 shows a graph in which the value of the analyteis assessed using similar calculations but in which the “referencingwavelength” is an absorbance trough (“b”) unaffected by theconcentration of the analyte. The “measuring wavelength” peak (“a”) ismeasured against a baseline.

EXAMPLES Example 1

[0094] Using a commercially available IR spectrometer (Nicolet 510)having a ZnSe crystal ATR plate (55 mm long, 10 mm wide, and 4 mm thick)we tested the inventive procedure. We calibrated the output of thespectrometer by comparing the IR signal to the values actually measuredusing one of the inventor's blood samples. The inventor used a bloodstick known as “Whisper Soft” by Amira Medical Co. and “GlucometerElite” blood glucose test strips sold by Bayer Corp. of Elkhart, Ind. Oneach of the various test days, the inventor took several test sticks andmeasured the glucose value of the resulting blood; the IR test was madeat the same approximate time.

[0095] As shown in the calibration curve of FIG. 6, the data are quiteconsistent. So, where the blood glucose concentration “B” is in (mg/dl)and “S” is the difference between the absorbance at the referencingregion and the measuring region as measured by the spectrometer:

B=[(1950)·S]−(17).

Example 2

[0096] In accordance with a clinical protocol, a diabetic was thentested. Curve 1 in FIG. 8 shows the IR absorbance spectrum of the testsubject's finger before eating (and after fasting overnight) and curve 2shows IR absorbance spectrum of the same individual after having eaten.Incidentally, insulin was administered shortly after the measurement ofcurve 2.

[0097] In any event, the significant difference in the two peak heightsat the 9.75 micrometer wavelength and the equality of the two IRabsorbance values at the 8.50 micrometer value shows the effectivenessof the procedure in measuring glucose level.

Example 3

[0098] That the inventive glucose monitoring device non-invasivelydetermines blood glucose level and quickly follows changes in that bloodglucose level is shown in FIG. 9. Using both the inventive procedure anda commercial glucose device, one of the inventors followed his glucoselevel for a single day. The blood sticks are considered to be accuratewithin 15% of the actual reading.

[0099] The results are shown in FIG. 9. Of particular interest is themeasurement just before 4:40 pm wherein the two values are essentiallythe same. A high sugar candy bar was eaten at about 4:45 pm andmeasurements of glucose level were taken using the inventive procedureat about 5:03, 5:18, 5:35 and 5:50. A blood was taken at 5:35 andreflected almost the same value as that measured using inventiveprocedure. Consequently, the procedure tracks that measured by the veryquickly.

[0100] This invention has been described and specific examples of theinvention have been portrayed. The use of those specifics is notintended to limit the invention in any way. Additionally, to the extentthere are variations of the invention with are within the spirit of thedisclosure and yet are equivalent to the inventions found in the claims,it is our intent that this patent will cover those variations as well.

We claim as our invention:
 1. An analyte level measurement devicecomprising: a.) an infrared source for emitting an IR beam into an ATRplate, said IR beam having components at least in the region of areferencing wavelength and a measuring wavelength, b.) said ATR platehaving a measurement surface for contact with said human skin surfaceand for directing said IR beam against said human skin surface, and c.)at least two IR sensors for simultaneously measuring absorbance of atleast said referencing wavelength and said measuring wavelength.